The overall aim of this One Health application is to accelerate the development of paramyosin (rSj97) and a newly discovered antigen (rSj68) as vaccines against human and bovine schistosomiasis japonica. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in 1.53 million DALYs lost per annum 1, and contributes to poor health and economic stagnation in endemic areas 2. Although schistosomiasis is effectively treated with praziquantel (PZQ), rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Most importantly, Schistosoma japonicum is a zoonosis with domesticated water buffalo (the key labor force for rice farming) suffering from the disease, as well as constituting a critical reservoir for continuing transmission to humans. In our recent work, we show that buffalo residing in our field site in Leyte, the Philippines have a prevalence of infection of 97%- underscoring the importance of these species for transmission to humans. Paramyosin was originally identified as the parasite target of antibodies generated in mice protectively vaccinated with S. mansoni schistosomula or adult worm extract 3. Our group conducted the pivotal study linking paramyosin and protection in S. japonicum 4. In four independent experiments, vaccination of mice with biochemically purified paramyosin (Sj97) resulted in 62%-86% (all P < 0.001) reduction in worm burden following cercarial challenge. We have conducted extensive immuno-epidemiology studies of Sj97 in a treatment-reinfection cohort of 616 S. japonicum infected individuals 5. We demonstrate a 30 to 41% lower intensity of reinfection (all P < 0.05) after praziquantel treatment in individuals with high Th2/Th1 cytokine ratios measured in PBMCs stimulated with Sj97. In this same cohort, we recently demonstrated that individuals with IgE but not IgG4 responses to rSj97 had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 but not IgE responses, even after adjusting for potential confounders (p=0.016) 6. We identified rSj68 using a novel differential screening approach to identify parasite antigens recognized by antibodies expressed by resistant, but not susceptible children 7. By immunofluorescence and immunogold electron microscopy, rSj68 localizes to the tegument and gastro-dermis of adult male and female worms. In a holoendemic site in the Philippines, individuals with high titer IgE anti-rSj68 had a 58% lower intensity of reinfection over 12 months of follow-up compared to individuals without these antibodies (n=616, P < 0.001). In the current application, we propose to accelerate the development of paramyosin and rSj68 as vaccines for human and bovine schistosomiasis by conducting safety and efficacy trials in water buffaloes. We will focus our studies on adjuvants that have already been tested and found safe in humans and animals, thus accelerating our development efforts toward a Phase I vaccination study in humans and Phase II studies in bovines. The deliverables of this program will be an adjuvant optimized, bivalent schistosome vaccine that is ready for human Phase I and bovine Phase II trials with safety data to support an FDA IND application. This vaccine would have a tremendous impact on One Health objectives, including: 1) improved animal health, 2) improved animal productivity, 3) improved farm output, 4) decreased transmission of schistsosomaisis to humans, and 5) improved human health due to both direct (human vaccination) and indirect (buffalo vaccination) effects.